PROJECT SUMMARY Cerebral amyloid angiopathy (CAA), characterized by the deposition of amyloid-? protein (A?) in the basement membrane of small arteries and capillaries of the leptomeninges and cerebral cortex, occurs sporadically or as a result of genetic mutations. CAA plays an important role in the multimorbidity of aging brains. In the early stages, CAA triggers cerebrovascular inflammation and causes microhemorrhages, vascular dysfunction and cognitive impairment; in advanced stages, CAA often leads to massive lobar hemorrhages. The incidence of sporadic CAA increases with age and it is a common pathological feature of brains with Alzheimer?s disease (AD). Currently there are no approved therapies to treat CAA. Blood brain barrier (BBB) dysfunction and impaired vascular health cause diminished A? clearance at the BBB and trigger CAA/AD. Strategies that remodel cellular trafficking at the BBB and improve vascular function are expected to enhance brain A? clearance, mitigate CAA/AD, and improve cognitive function. High levels of circulating high-density lipoprotein (HDL) and its main protein component, apoA-I, reduce the risk of cardiovascular disease. Compelling evidence indicates that HDL/apoA-I also modulates neurobiological functions. High levels of HDL/apoA-I are associated with superior cognitive function in the elderly, whereas low levels of HDL/apoA-I increase the risk for AD and intracerebral hemorrhage. In animal models, manipulation of HDL biogenesis pathways modifies the development of AD-like pathology and behavior. In particular, we have shown that overexpression of human apoA-I rescues cognitive function in AD mice by attenuating CAA and neuroinflammation. Consistently, others have shown that deletion of apoA-I increases CAA and exacerbates cognitive deficits in AD mice. In preliminary studies, we found that a unique HDL/apoA-I mimetic peptide known as 4F, which has advanced into clinical trials for cardiovascular disease, augments HDL function of AD mice, effectively inhibits A? aggregation, protects cultured neurons against A?-induced cytotoxicity, efficiently penetrates the BBB, and promotes the efflux of A? across the BBB. Thus, we propose to repurpose the peptide for CAA/AD and hypothesize that treatment with the HDL mimetic peptide facilitates the clearance of cerebrovascular A?, mitigates CAA and other AD-related pathologies, and improves cerebrovascular and cognitive functions. Three specific aims are proposed to test this hypothesis by using a combination of innovative in vivo and in vitro approaches. Aim 1 is to determine the mechanisms by which the HDL mimetic peptide modulates cerebrovascular A? clearance. Aim 2 is to evaluate the impact of the HDL mimetic peptide on cerebrovascular function using non-invasive imaging/tonometric technologies in both wild type and CAA/AD mice. Aim 3 is to assess the efficacy of the HDL mimetic peptide to mitigate CAA- associated cognitive deficits and neuropathologies in CAA/AD mouse models. Results from these proposed studies are expected to provide a novel approach to combat CAA/AD.